Lacosamide is a chiral molecule useful in treating convulsions and pain. It was approved by USFDA in 2008 and is marketed by UCB under the trade name VIMPAT®. It is chemically (R)-2-acetamido-N-benzyl-3-methoxypropionamide (formula I) having the following structure:

The U.S. Pat. No. 5,773,475 describes three schemes for the preparation of Lacosamide. Scheme-1 involves conversion of D-serine to its methyl ester hydrochloride followed by amidation with benzylamine. Acetylation of the benzylamide followed by Williamson etherification resulted in Lacosamide.

In this scheme, the benzylamide intermediate is obtained with poor chiral purity due to racemization. Also, methylation stage involves the use of methyl iodide, which is a low boiling, hazardous reagent, and silver oxide, which is expensive. The scheme-2 involves acetylation of D-serine followed by coupling with benzylamine using mixed anhydride method and finally O-methylation using methyl iodide and silver oxide.

The third method (Scheme-3) involves protection of the amino group of D-serine with benzyloxycarbonyl (Cbz), followed by methylation. This is followed by hydrolysis, benzyl amidation, Cbz-deprotection and N-acetylation.

The Scheme-3 is complicated as it consists of a large number of steps. It involves protection and deprotection of the amino group. In addition, the methylation step results in two methylations, methylation of alcoholic group and esterification of the carboxylic group, requiring hydrolysis of the ester before coupling with benzylamine.
Later UCB patent, U.S. Pat. No. 7,884,134, described a process involving N-Boc-D-serine and methylation using a phase-transfer catalyst. Another modification described is the use of butyllithium/dimethyl sulfate as the methylating agent. Ranbaxy laboratories reported a process (U.S. Pat. No. 8,093,426) wherein a trityl moiety was used as bulky protecting group to minimize nucleophilic attack on the chiral carbon to suppress racemization. A divisional patent, U.S. Pat. No. 8,378,142, claimed the trityl intermediate, N-benzyl-O-methyl-N2-trityl-D-serinamide.

U.S. Pat. No. 8,853,439 describes a process which involves protecting both amino and alcoholic groups of D-serine (Scheme-4).

U.S. Pat. No. 8,598,386 describes a process which involves condensation of Boc-D-serine with benzylamine using 2,4,6-tripropyl-2,4,6-trioxo-1,3,5,2,4,6-trioxatriphosphorinane (T3P®) as a coupling agent (Scheme-5).

While all the above methods started from D-serine as the starting material, the U.S. Pat. No. 8,796,488 describes a process from (DL)-serine involving final resolution using 2-(S)-chloro mandelic acid (Scheme-6).

A new application from UCB, US 2014/0018577 describes a process via resolution of O-methyl-DL-serine using a chiral acid or through enzyme, followed by acetylation and condensation with benzylamine after activation using alkyl chloroformate (Scheme-7).

The starting compound, O-methyl-DL-serine is a special chemical and cannot be prepared easily from DL-serine. Apart from using expensive resolving agents or enzymes for resolution, the final step of condensation with benzylamine using isobutylchloroformate requires very low temperature (−20 to −10° C.). The methods based on (DL)-serine involve several steps and are expensive even if the unwanted isomer is recovered.
Because of the enumerated drawbacks of the above-mentioned processes, there is a need for developing an improved process.